Synthesis of the key intermediate, diethyl 2-acetylamino-2-(2-(4- octanoylphenyl)ethyl)propane-1,3-dioate, of the immunomodulatory agent FTY720 (fingolimod)

Article abstract of DOI:10.1248/cpb.56.595

The key intermediate, diethyl 2-acetylamino-2-(2-(4-octanoylphenyl)ethyl) propane-1,3-dioate (13), for the immunomodulatory agent FTY720 (2: fingolimod) was synthesized via Michael addition of diethyl(acetylamino) malonate (6) to 4-octanoylstyrene (12).

Full text of DOI:10.1248/cpb.56.595

April 2008
Notes
Chem. Pharm. Bull. 56(4) 595—597 (2008)
595
Synthesis of the Key Intermediate, Diethyl 2-Acetylamino-2-(2-(4-
octanoylphenyl)ethyl)propane-1,3-dioate, of the Immunomodulatory
Agent FTY720 (Fingolimod)
Norimasa MATSUMOTO,a,1) Ryoji HIROSE,a,2) Shigeo SASAKI,a,3) and Tetsuro FUJITA*,b,4)
a Research Laboratory, Taito Co., Ltd.; 1–26 Higashi Shiriike-Shinmachi, Nagata-ku, Kobe 653–0023, Japan: and b Faculty
of Pharmaceutical Sciences, Setsunan University; 45–1 Nagaotoge-cho, Hirakata, Osaka 573–0101, Japan.
Received October 26, 2007; accepted January 18, 2008; published online January 22, 2008
The key intermediate, diethyl 2-acetylamino-2-(2-(4-octanoylphenyl)ethyl)propane-1,3-dioate (13), for the
immunomodulatory agent FTY720 (2: fingolimod) was synthesized via Michael addition of diethyl(acetyl-
amino)malonate (6) to 4-octanoylstyrene (12).
Key words FTY720; immunomodulatory agent; Michael addition; fingolimod
Members of our group previously isolated a potent im- group.11,12,28) We subsequently patented a more convenient
munosuppressant, ISP-I (1) (Chart 1), from the culture broth synthesis of 2 via routes including Michael addition (3→4→
of Isaria sinclairii (ATCC24400), and showed that it could 8→9→[12]→13→7→2, 10→11→13→7→2).29) Other syn-
suppress both lymphocyte proliferation in the mouse allo- thetic routes to 2 were subsequently developed.30—33) Here,
geneic mixed lymphocyte reaction (MLR) system in vitro we describe the convenient synthesis of the key intermediate,
and generation of allo-reactive cytotoxic T lymphocytes in diethyl 2-acetylamino-2-(2-(4-octanoylphenyl)ethyl)propane-
mice in vivo.5) Compound 1 is identical with the antifungal 1,3-dioate (13) in detail.
antibiotics myriocin6,7) and thermozymocidin,8,9) which are
To improve Adachi’s method, we focused on the condensa-
produced by Myriococcum albomyces and Mycelia sterilia, tion of 5 and 6. During this condensation, nucleophilic sub-
respectively. The structure of 1 was subsequently modified in stitution occurs as the main reaction and elimination as a side
order to reduce its toxicity, to improve its physicochemical reaction to afford 7 and the styrene derivative, respectively.
properties and to identify the essential structure for immuno- Therefore, 5 was replaced with 4ꢀ-(2-haloethyl)octanophe-
suppressive activity,10) and a candidate compound, FTY720 none. Even if 4ꢀ-(2-haloethyl)octanophenone affords the
(2: 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol hy- styrene 1234) by elimination, it is expected that 12 will un-
drochloride, fingolimod), was obtained.11—14) Compound 2 dergo Michael-type nucleophilic attack by the anion of the
does not impair the activation, proliferation or effector func- malonate 6 to give the intermediate 13. Further, the synthesis
tions of T- and B-cells, in contrast with established immuno- can be shortened, because 4ꢀ-(2-haloethyl)octanophenone
suppressants (cyclosporin, tacrolimus, etc.). It has been pro- can be derived from phenethyl halide, such as phenethyl bro-
posed that 2 is phosphorylated by sphingosine kinase, and mide (10). First, the iodide 9 was synthesized from the ac-
the product, FTY720 monophosphate, acts as an agonist of etate 4 by deprotection and iodination, and condensed with 6
sphingosine-1-phosphate (S1P) and modulates immune re- to afford 13. At the same time, it was found that hydrogen io-
sponse by sequestering lymphocytes from peripheral blood to dide was eliminated from 9 to give the styrene 12 (equivalent
the secondary lymphoid tissues.15—18) Thus, 2 has a unique to half the total amount of product), which was condensed
mechanism of action and is expected to be useful for im- with 6 to give 13 by Michael addition reaction. Next, the bro-
munosuppression following organ transplantation and for the mide 1134) derived from 10 was examined. It was found that
treatment of various diseases, including multiple sclerosis,16) the elimination and condensation reactions could be run in
rheumatoid arthritis,19) atopic dermatitis,20) and myasthenia one pot (see Experimental) to afford the key intermediate 13,
gravis,21) based on findings in animal models. Clinical trials which was hydrogenated to Adachi’s intermediate, 7.
of 2 in renal transplantation22—26) and multiple sclerosis pa-
In conclusion, we have developed a convenient synthesis
of the key intermediate, diethyl 2-acetylamino-2-(2-(4-oc-
tients27) have been performed.
Adachi et al. first synthesized 2 via the route 3→4→→ tanoylphenyl)ethyl)propane-1,3-dioate (13), of FTY720 (2:
→→5→7→2, as shown Chart 2, in cooperation with our fingolimod) from phenethyl bromide (10) in 55% overall
yield. Adachi’s method provided the common intermediate,
7, from 3 in 6 steps with 18% yield,11,12) while the new
method afforded 7 from 10 (via 13) in only 3 steps with 41%
yield.
Experimental
General Information Melting points were determined on a Yanagimoto
micro melting point apparatus without correction. IR spectra were taken on
a Shimadzu FTIR-8400 infrared spectrophotometer. Mass spectra (EI-MS,
FAB-MS) were taken on a Shimadzu QP-2000 and JEOL JMS-700T spec-
trometers. 1H-NMR spectra were taken on a JEOL EX-270, JEOL JNM-
GX400, and Varian UNITY plus 500 spectrometers with TMS as an internal
standard; chemical shifts are reported in parts per million. TLC was per-
Chart 1
formed on aluminum-seated silica gel 60 F254 (Merck). For column chro-
∗ To whom correspondence should be addressed. e-mail: tetsuro.fujita@ma1.seikyou.ne.jp
© 2008 Pharmaceutical Society of Japan

596
Vol. 56, No. 4
Chart 2
matography, silica gel (70—230 mesh, Merck) was used. Organic solvent filtered through silica gel, and the eluate was evaporated to give 9 (175 g,
extracts were dried over anhydrous magnesium sulfate, and evaporation of 88%) as a white solid: mp 36.5 °C; IR nmax (KBr) cmꢁ1: 2950, 2920, 2850,
solvents was performed under reduced pressure.
4ꢀ-(2-Hydroxyethyl)octanophenone (8) To a solution of octanoyl chlo- ArH), 7.26 (2H, d, Jꢂ8.3 Hz, ArH), 3.35 (2H, t, Jꢂ7.3 Hz, CH2I), 3.22 (2H,
1680, 1600, 1230; 1H-NMR (500 MHz, CDCl3) d: 7.90 (2H, d, Jꢂ8.3 Hz,
ride (216 g, 1.33 mol) and phenethyl acetate (3, 285 g, 1.74 mol) in 1,2-
dichloroethane (900 ml) was added AlCl3 (372 g, 2.80 mol) under ice cool-
ing. The mixture was stirred at room temperature for 2.5 h, then poured into
t, Jꢂ7.3 Hz, PhCH2), 2.92 (2H, t, Jꢂ7.6 Hz, COCH2), 1.71 (2H, quintet,
Jꢂ7.1 Hz, COCH2CH2), 1.36—1.25 (8H, m, (CH2)4CH3), 0.86 (3H, t,
Jꢂ7.1 Hz, CH3); EI-MS m/z: 274 ([I(CH2)2C6H4C(OH)ꢂCH2]ꢃ). HR-MS
water. The extracted organic solution was washed with water, dried, and (EI) m/z: 358.0789 (Calcd for C16H23OI: 358.0794). HR-MS (FABꢃ) m/z:
evaporated. The residue was dried in vacuo to give a colorless oil (280 g) 359.0879 (Calcd for C16H24OI: 359.0872).
containing 2-(4-octanoylphenyl)ethyl acetate 4 as the major component. To
this oil (280 g) in MeOH (200 ml) was added 28% sodium methoxide (5.3 g,
82.8 mmol) in MeOH (18.8 ml), and the mixture was stirred at room temper-
ature for 1 h. A suspension of Amberlite IR-120B in MeOH (98 ml) was
4-Octanoylstyrene (12) and Diethyl 2-Acetylamino-2-(2-(4-octanoyl-
phenyl)ethyl)propane-1,3-dioate (13) To a solution of diethyl (acetyl-
amino)malonate (6, 9.09 g, 41.9 mmol) in dried DMF (30 ml) was added
60% sodium hydride (1.23 g, 30.8 mmol) under ice cooling, and the mixture
added to the reaction mixture, and removed by filtration, then the filtrate was was stirred at room temperature for 1 h under a nitrogen atmosphere. To this
evaporated. The residue was recrystallized from n-hexane–EtOAc (10 : 1) to mixture was added 9 (5.0 g, 14.0 mmol) in dried DMF (15 ml) under a nitro-
give 8 (138 g, 43%) as colorless plates: mp 47.4 °C; IR nmax (KBr) cmꢁ1
:
gen atmosphere, and the whole was stirred at 60 °C for 2 h, poured into ice
3260, 2910, 2850, 1680; 1H-NMR (500 MHz, CDCl3) d: 7.91 (2H, d, water, and extracted with Et2O. The extract was washed with brine, dried
Jꢂ8.5 Hz, ArH), 7.32 (2H, d, Jꢂ8.5 Hz, ArH), 3.90 (2H, t, Jꢂ6.6 Hz, and evaporated. The residue was chromatographed on silica gel with n-
CH2OH), 2.94 (2H, t, Jꢂ7.3 Hz, COCH2), 2.93 (2H, t, Jꢂ6.6 Hz, PhCH2), hexane to give 12 (1.5 g, 47%) as a white powder and with n-hexane–EtOAc
1.72 (2H, quintet, Jꢂ7.3 Hz, COCH2CH2), 1.59 (1H, br s, OH), 1.40—1.26 (3 : 1) to give 13 (3.2 g, 51%) as a white powder.
(8H, m, (CH2)4CH3), 0.88 (3H, t, Jꢂ7.1 Hz, CH3); EI-MS m/z: 248 ([M]ꢃ).
13 from 12 To a solution of diethyl(acetylamino)malonate (6, 4.25 g,
4ꢀ-(2-Iodoethyl)octanophenone (9) To a solution of 8 (137 g, 0.55 19.6 mmol) in dried DMF (30 ml) was added 60% sodium hydride (0.57 g,
mol), imidazole (53 g, 0.78 mol), and triphenylphosphine (174 g, 0.66 mol) 14.3 mmol) under ice cooling, and the mixture was stirred at room tempera-
in EtOAc (550 ml) was added iodine (197 g, 0.78 mol) under ice cooling. ture for 0.5 h under a nitrogen atmosphere. Then 12 (1.5 g, 6.5 mmol) in
The mixture was stirred at room temperature for 1 h, then diluted with dried DMF (15 ml) was added under a nitrogen atmosphere. The mixture
EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried
was stirred at 60 °C for 6 h, and at room temperature for 2 d, then poured
and evaporated. The residue was suspended in n-hexane–EtOAc (10 : 1), and into ice water, and extracted with Et2O. The extract was washed with brine,

April 2008
597
dried and evaporated. The residue was chromatographed on silica gel with n-
hexane–EtOAc (3 : 1) to give 13 (2.3 g, 79%) as a white powder.
4) Present address: Research Institute for Production Development; 15
Shimogamo Morimoto-cho, Sakyo-ku, Kyoto 606–0805, Japan.
5) Fujita T., Inoue K., Yamamoto S., Ikumoto T., Sasaki S., Toyama R.,
Chiba K., Hoshino R., Okumoto T., J. Antibiot., 47, 208—215 (1994).
6) Kluepfel D., Bagli J., Baker H., Charest M.-P., Kudelski A., Sehgal S.
N., Vezina C., J. Antibiot., 25, 109—115 (1972).
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(1973).
8) Craveri R., Manachini P. L., Aragozzini F., Experientia, 28, 867—868
(1972).
13 from 10 To a solution of phenethyl bromide (10, 5.00 g, 27.0 mmol)
and octanoyl chloride (4.83 g, 29.1 mmol) in CH2Cl2 (40 ml) was added
AlCl3 (3.67 g, 27.6 mol) at ꢁ20 °C. The mixture was stirred at ꢁ20 °C for
1 h and at room temperature overnight, then poured into ice water, and ex-
tracted with Et2O. The extract was washed successively with 1 N HCl, brine,
saturated NaHCO3 aqueous solution and brine. The extract was dried and
evaporated. The residue was dissolved in n-hexane–EtOAc (20 : 1), and the
solution was filtered through silica gel and evaporated to give a pale yellow
oil (6.96 g) containing 4ꢀ-(2-bromoethyl)octanophenone (11) as the major
component.
9) Aragozzini F., Manachini P. L., Craveri R., Rindone B., Scolastico C.,
Tetrahedron, 28, 5493—5498 (1972).
To this oil (0.50 g) in dried EtOH (2 ml) was added sodium ethoxide
(0.16 g, 2.35 mmol) under a nitrogen atmosphere, and the mixture was
stirred at 60 °C for 1 h, and then DMF (10 ml), 6 (1.05 g, 4.84 mmol) and
10) Fujita T., Hirose R., Yoneta M., Sasaki S., Inoue K., Kiuchi M., Hirase
S., Chiba K., Sakamoto H., Arita M., J. Med. Chem., 39, 4451—4459
(1996).
sodium ethoxide (0.25 g, 3.68 mmol) were added to the mixture under a ni- 11) Adachi K., Kohara T., Nakao N., Arita M., Chiba K., Mishina T.,
trogen atmosphere. The mixture was stirred at 60 °C overnight, then poured Sasaki S., Fujita T., Bioorg. Med. Chem. Lett., 5, 853—856 (1995).
into ice water, and extracted with Et2O. The extract was washed with brine, 12) Kiuchi M., Adachi K., Kohara T., Minoguchi M., Hanano T., Aoki Y.,
dried, and evaporated. The residue was chromatographed on silica gel with
Mishina T., Arita M., Nakao N., Ohtsuki M., Hoshino Y., Teshima K.,
n-hexane–EtOAc (3 : 1) to give 13 (0.48 g, 55%) as a white powder.
Chiba K., Sasaki S., Fujita T., J. Med. Chem., 43, 2946—2961 (2000).
Compound 11: IR nmax (KBr) cmꢁ1: 2960, 2930, 2860, 1690 (CꢂO), 13) Fujita T., Farumashia, 33, 591—593 (1997).
1
1610, 1410, 1260, 1220, 1180; H-NMR (500 MHz, CDCl3) d: 7.92 (2H, d, 14) Kiuchi M., Farumashia, 43, 673—677 (2007).
Jꢂ8.3 Hz, ArH), 7.30 (2H, d, Jꢂ8.3 Hz, ArH), 3.59 (2H, t, Jꢂ7.4 Hz,
BrCH2), 3.22 (2H, t, Jꢂ7.4 Hz, BrCH2CH2), 2.90 (2H, t, Jꢂ7.4 Hz,
COCH2), 1.73 (2H, quintet, Jꢂ7.4 Hz, COCH2CH2), 1.38—1.27 (8H, m,
(CH2)4CH3), 0.88 (3H, t, Jꢂ7.1 Hz, CH3); EI-MS m/z: 312 and 310 ([M]ꢃ).
15) Mandala S., Hajdu R., Bergstrom J., Quackenbush E., Xie J., Milligan
J., Thornton R., Shei G.-J., Card D., Keohane C., Rosenbach M., Hale
J., Lynch C. L., Rupprecht K., Parsons W., Rosen H., Science, 296,
346—349 (2002).
Compound 12: mp 60.5 °C (lit.34) mp 62—63 °C). IR nmax (KBr) cmꢁ1
:
16) Brinkmann V., Davis M. D., Heise C. E., Albert R., Cottens S., Hof R.,
Bruns C., Prieschl E., Baumruker T., Hiestand P., Foster C. A.,
Zollinger M., Lynch K. R., J. Biol. Chem., 277, 21453—21457 (2002).
2920, 2850, 1670, 1470, 1410, 1320, 1280, 990, 910, 860; 1H-NMR
(400 MHz, CDCl3) d: 7.92 (2H, d, Jꢂ8.3 Hz, ArH), 7.47 (2H, d, Jꢂ8.3 Hz,
ArH), 6.75 (1H, dd, Jꢂ17.6, 10.9 Hz, CHCH2), 5.86 (1H, d, Jꢂ17.7 Hz, 17) Chiba K., Yanagawa Y., Masubuchi Y., Kataoka H., Kawaguchi T.,
CHaꢂ), 5.38 (1H, d, Jꢂ10.9 Hz, CHbꢂ), 2.90 (2H, t, Jꢂ7.3 Hz, COCH2),
Ohtsuki M., Hoshino Y., J. Immunol., 160, 5037—5044 (1998).
1.73 (2H, quintet, Jꢂ7.3 Hz, COCH2CH2), 1.35—1.29 (8H, m, (CH2)4CH3), 18) Yanagawa Y., Sugahara K., Kataoka H., Kawaguchi T., Masubuchi Y.,
0.88 (3H, t, Jꢂ6.8 Hz, CH3); EI-MS m/z: 230 ([M]ꢃ).
Chiba K., J. Immunol., 160, 5493—5499 (1998).
Compound 13: mp 79.0 °C; IR nmax (KBr) cmꢁ1: 3250, 2930, 2850, 1750, 19) Matsuura M., Imayoshi T., Okumoto T., Int. J. Immunopharmacol., 22,
1
1680, 1650, 1520, 1260, 1220, 1200; H-NMR (500 MHz, CDCl3) d: 7.84
323—331 (2000).
(2H, d, Jꢂ8.3 Hz, ArH), 7.21 (2H, d, Jꢂ8.3 Hz, ArH), 6.75 (1H, br s, NH), 20) Kohno T., Tsuji T., Hirayama K., Watabe K., Matsumoto A., Kohno T.,
4.20 (2H, q, Jꢂ6.8 Hz, OCH2CH3), 4.19 (2H, q, Jꢂ7.1 Hz, OCH2CH3), 2.90 Fujita T., Biol. Pharm. Bull., 27, 1392—1396 (2004).
(2H, t, Jꢂ7.3 Hz, COCH2), 2.69 (2H, m, PhCH2), 2.51 (2H, m, PhCH2CH2), 21) Kohno T., Tsuji T., Hirayama K., Iwatsuki R., Hirose M., Watabe K.,
1.96 (3H, s, NHCOCH3), 1.69 (2H, quintet, Jꢂ7.3 Hz, COCH2CH2), 1.32
(2H, m, CO(CH2)2CH2), 1.27 (6H, m, (CH2)3CH3), 1.23 (6H, t, Jꢂ
Yoshikawa H., Kohno T., Matsumoto A., Fujita T., Hayashi M., Biol.
Pharm. Bull., 28, 736—739 (2005).
7.1 Hz, OCH2CH3ꢄ2), 0.86 (3H, t, Jꢂ6.8 Hz, CH3); EI-MS m/z: 402 22) Budde K., Schmouder R. L., Brunkhorst R., Nashan B., Lucker P. W.,
([MꢁOCH2CH3]ꢃ). HR-MS (EI) m/z: 447.2614 (Calcd for C25H37NO6:
447.2620).
Mayer T., Choudhury S., Skerjanec A., Kraus G., Neumayer H. H., J.
Am. Soc. Nephrol., 13, 1073—1083 (2002).
Diethyl 2-Acetylamino-2-(2-(4-octylphenyl)ethyl)propane-1,3-dioate 23) Kahan B. D., Karlix J. L., Ferguson R. M., Leichtman A. B., Mul-
(7) A solution of 13 (923 g, 2.06 mol) in EtOH (10 l) was stirred under a
gaonkar S., Gonwa T. A., Skerjanec A., Schmouder R. L., Chodoff L.,
hydrogen atmosphere in the presence of 5% Pd/C (138 g) overnight. The cat-
Transplantation, 76, 1079—1084 (2003).
alyst was removed by filtration and the filtrate was evaporated to give a 24) Tedesco-Silva H., Mourad G., Kahan B. D., Boira J. G., Weimar W.,
residue. This was recrystallized from n-hexane to give 7 (670 g, 75%), which
Mulgaonkar S., Nashan B., Madsen S., Charpentier B., Pellet P., Van-
renterghem Y. Transplantation, 77, 1826—1833 (2004).
was identical with an authentic sample of 712) (IR, 1H-NMR, MS), as a white
powder: mp 61.0 °C; IR nmax (KBr) cmꢁ1: 3300, 2920, 2850, 1750, 1650, 25) Salvadori M., Budde K., Charpentier B., Klempnauer J., Nashan B.,
1
1520, 1220, 1200; H-NMR (270 MHz, DMSO-d6) d: 8.32 (1H, br s, NH),
7.08 (2H, d, Jꢂ7.9 Hz, ArH), 7.02 (2H, d, Jꢂ7.9 Hz, ArH), 4.13 (4H, q,
Pallardo L. M., Eris J., Schena F. P., Eisenberger U., Rostaing L.,
Hmissi A., Aradhye S., Am. J. Transplant., 12, 2912—2921 (2006).
Jꢂ7.3 Hz, OCH2CH3ꢄ2), 2.52 (4H, m, Jꢂ7.3 Hz, PhCH2ꢄ2), 2.37 (2H, m, 26) Tedesco-Silva H., Pescovitz M. D., Cibrik D., Rees M. A., Mulgaonkar
PhCH2CH2C), 1.94 (3H, s, NHCOCH3), 1.52 (2H, m, PhCH2CH2), 1.24
(10H, m, (CH2)5CH3), 1.15 (6H, t, Jꢂ7.3 Hz, OCH2CH3ꢄ2), 0.85 (3H, t,
Jꢂ6.6 Hz, CH3); EI-MS m/z: 433 ([M]ꢃ), 388 ([MꢁOCH2CH3]ꢃ); Anal.
S., Kahan B. D., Gugliuzza K. K., Rajagopalan P. R., Esmeraldo R. de
M., Lord H., Salvadori M., Slade J. M., Transplantation, 82, 1689—
1697 (2006).
Calcd for C25H39NO5: C, 69.25; H, 9.06; N, 3.23; O, 18.45. Found: C, 69.48; 27) Kappos L., Antel J., Comi G., Montalban X., O’Connor P., Polman C.
H, 8.76; N, 3.21; O, 18.55.
H., Haas T., Korn A. A., Karlsson G., Radue E. W., N. Engl. J. Med.,
355 1124—1140 (2006).
Acknowledgment The authors are grateful to Dr. S. Yamaguchi of the 28) Fujita T., Sasaki S., Yoneta M., Mishina T., Adachi K., Chiba K.,
Faculty of Pharmaceutical Sciences, Setsunan University for measurement
PCT/WO94/08943.
of the mass spectra of compounds 9 and 13.
29) Hirase S., Sasaki S., Hirose R., Yoneta M., Fujita T., PCT/WO99/1419.
30) Durand P., Peralba P., Sierra F., Renaut P., Synthesis, 2000, 505—506
(2000).
References and Notes
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